The brain is unique in that it is the only organ completely surrounded by bone. This establishes a fixed volume that limits the brain's ability to expand. Of the contents within the skull, 80% is occupied by brain tissue, 10% by cerebral spinal fluid (CSF), and 10% by blood. There are numerous injuries or pathological mechanisms that can predispose an individual to intracranial hypertension. Most commonly, this condition results from cerebral edema. Cerebral edema or brain swelling can be precipitated by strokes, tumors, traumatic brain injury, and bleeding (“insults”). Following these insults, the brain begins to swell and dispels first the CSF that serves to cushion the brain. Expansion beyond the space occupied by the CSF will start to reduce cerebral blood flow, leading to potentially permanent ischemic (oxygen deprivation) injury, or cause the brain itself to herniate across structures or through foramina (openings or orifices, as in bone tissue of the skull), resulting in death.
Over the years, medical professionals have developed devices (i.e. external ventricular drain) and therapies (i.e. steroids, hyperventilation, and hypertonic fluid) to help prevent and treat intracranial hypertension. One of the most routinely employed therapies is the use of hypertonic intravenous infusions (i.e. 3%, 7.5%, 10%, 23.4% saline or 20% mannitol). These infusions take advantage of the selectivity of the blood brain barrier, a semipermeable layer that tightly and slowly regulates the transfer of electrolytes in and out of the brain while allowing water to cross freely and rapidly via osmosis. By infusing solutions that are osmotically more concentrated than the brain's parenchyma (refer to Table 1), providers can remove water from the brain tissue and deliver it to the blood where it can be eliminated via the kidneys, in the form of urine, or by dialysis.
The above treatment is essentially a two-step process. Water must be drawn out of the brain and then eliminated from the body. Thus, the ideal fluid therapy must at a minimum be more osmotically concentrated than blood and brain tissue, but non-toxic to the kidneys. Current IV fluids consist of various hypertonic sodium chloride solutions or 20% mannitol. However, all of these fluids are capable of causing profound electrolyte abnormalities and acute renal failure, which are counterproductive in the management of cerebral edema.
For example, 3% saline solution has a total osmolarity of 1026 mEq/L and is made from equal parts sodium and chloride (513 mEq/L of each). This fluid is often used to rapidly increase the total serum and sodium osmolarity of the patient's blood (FIG. 1). Following this relatively rapid alteration, providers will use intermittent or continuous infusions and frequent laboratory evaluation to maintain and monitor, respectively, the desired sodium and serum osmolarity goals. Ultimately, the utilization of any hypertonic saline will cause a greater perturbation in the patient's chloride level than the sodium level. Normal serum chloride concentrations are about 104 mEq/L±5 mEq/L while sodium levels are about 140 mEq/L±5 mEq/L. Thus, other things being equal, the infusion of a solution that is equal parts sodium and chloride will cause a larger proportional increase in the patient's chloride level than the sodium level at equilibrium.
The more profound proportional increase in serum chloride concentration has many notable effects. The decrease in the proportional difference between sodium and chloride, due to the greater increase in chloride relative to sodium, results in a hyperchloremic metabolic acidosis due to a reduction in the strong ion difference. As the patient's blood becomes more acidemic, numerous systems are affected. Perhaps most concerning, however, is that acidemia can cause cerebral vascular dilation, potentially increasing the volume of blood and the overall pressure within the skull. Compared to balanced intravenous fluids, saline formulations case greater hemodynamic instability, a reduced cardiac index, a more altered microcirculation, and more severe organ dysfunction (Orbegozo, D., MD, Effects of Different Crystalloid Solutions on Hemodynamics, Peripheral Perfusion, and the Microcirculation in Experimental Abdominal sepsis; Anesthesiology 10, 2016, Vol. 125, pages 744-754).
Compared to the rest of the body's organs and capillary beds, the renal vasculature is tightly controlled by the serum chloride level (Wilcox, C S, Regulation of renal blood flow by plasma chloride; J. Clin. Invest., 1983, March; 71(3); pages 726-735). Increases in serum chloride concentrations can cause significant reductions in renal blood flow in a dose dependent manner. There are few physiologic and pathologic conditions that cause elevations in a patient's serum chloride level as those seen with hypertonic saline. Combined with the fluid restriction that frequently follows the initiation of hypertonic therapy (as current maintenance fluids are all hypotonic relative to frequently prescribed hyperosmolar goals), the hyperchloremic state puts the patient at an increased risk for acute kidney dysfunction and injury, which can greatly complicate the management of intracranial hypertension.
Based on the aforementioned discussion, there is a need for improved intravenous (IV) fluid mixtures for the treatment of patients at risk for or suffering from intracranial hypertension which reduce the risks associated with hyperchloremic metabolic acidosis. All current therapies require that physicians balance the risks of administering suboptimal IV fluids with the benefits of reducing brain swelling.